The purpose of this exploratory grant proposal is to develop and test a novel silicon-based biocapsule system for implanting neuronal xenografts. The proposal represents an interdisciplinary effort in which the fundamental problem of immunorejection of xenogeneic brain transplantation is approached from an engineering perspective and tested with functional paradigms in neuroscience. Biocapsules for neurosecretory cells will be micromachined from silicon to possess pores in the tens of nanometer range that will allow for free diffusion of neurotransmitter and essential nutrients but not antibodies and complement components. The ability of such permselective biocapsules to function as neurosecretory elements will be tested within the olivocerebellar system maintained under highly-controlled conditions in vitro, in which well- defined biophysical parameters can be used to assess the functionality of neurotransmitter release from encapsulated cell cultures. The specific aims of the proposal are: 1) to determine whether and how long chemically-specific neuronal populations can be cultured in micro fabricated permselective environments and retain function; 2) to integrate an active element into micro fabricated biocapsules in order to depolarize encapsulated neurons and induce neurotransmitter release on demand; 3) to determine whether and how long GABAergic or serotonergic neurons encapsulated within micro fabricated biocapsules can functionally affect extra-capsular neurons maintained in vitro; and 4) to determine whether delivery of specific neurotransmitters using stimulation biocapsules implanted into the brain in vivo can remediate a neurological disorder in an animal model. It is anticipated that the successful development of this silicon biocapsule for neuronal encapsulation and neurotransmitter release will provide a new paradigm for xenogeneic transplantation of tissue into the brain and other organ systems.